Charles Darwin University Population Pharmacokinetic ... RESEARCH ARTICLE Population Pharmacokinetic

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  • Charles Darwin University

    Population Pharmacokinetic Properties of Piperaquine in Falciparum Malaria

    An Individual Participant Data Meta-Analysis

    Hoglund, Richard M.; Workman, Lesley; Edstein, Michael D.; Thanh, Nguyen Xuan; Quang, Nguyen Ngoc; Zongo, Issaka; Ouedraogo, Jean Bosco; Borrmann, Steffen; Mwai, Leah; Nsanzabana, Christian; Price, Ric N.; Dahal, Prabin; Sambol, Nancy C.; Parikh, Sunil; Nosten, Francois; Ashley, Elizabeth A.; Phyo, Aung Pyae; Lwin, Khin Maung; McGready, Rose; Day, Nicholas P J; Guerin, Philippe J.; White, Nicholas J.; Barnes, Karen I.; Tarning, Joel Published in: PLoS Medicine

    DOI: 10.1371/journal.pmed.1002212

    Published: 10/01/2017

    Document Version Publisher's PDF, also known as Version of record

    Link to publication

    Citation for published version (APA): Hoglund, R. M., Workman, L., Edstein, M. D., Thanh, N. X., Quang, N. N., Zongo, I., Ouedraogo, J. B., Borrmann, S., Mwai, L., Nsanzabana, C., Price, R. N., Dahal, P., Sambol, N. C., Parikh, S., Nosten, F., Ashley, E. A., Phyo, A. P., Lwin, K. M., McGready, R., ... Tarning, J. (2017). Population Pharmacokinetic Properties of Piperaquine in Falciparum Malaria: An Individual Participant Data Meta-Analysis. PLoS Medicine, 14(1), 1-23. [e1002212].

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    Population Pharmacokinetic Properties of

    Piperaquine in Falciparum Malaria: An

    Individual Participant Data Meta-Analysis

    Richard M. Hoglund1,2,3, Lesley Workman1,4, Michael D. Edstein5, Nguyen Xuan Thanh6,

    Nguyen Ngoc Quang7, Issaka Zongo8,9, Jean Bosco Ouedraogo8, Steffen Borrmann10,11,

    Leah Mwai10,12, Christian Nsanzabana1,3, Ric N. Price1,3,13, Prabin Dahal1,3, Nancy

    C. Sambol14, Sunil Parikh15, Francois Nosten3,16, Elizabeth A. Ashley16, Aung

    Pyae Phyo16, Khin Maung Lwin16, Rose McGready3,16, Nicholas P. J. Day2,3, Philippe

    J. Guerin1,3, Nicholas J. White2,3, Karen I. Barnes1,4, Joel Tarning1,2,3*

    1 WorldWide Antimalarial Resistance Network, Oxford, United Kingdom, 2 Mahidol Oxford Tropical Medicine

    Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand, 3 Centre for Tropical

    Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom,

    4 Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South

    Africa, 5 Department of Drug Evaluation, Australian Army Malaria Institute, Brisbane, Queensland, Australia,

    6 Department of Malaria, Military Institute of Hygiene and Epidemiology, Hanoi, Viet Nam, 7 Department of

    Infectious Diseases, Military Hospital 108, Hanoi, Viet Nam, 8 Institut de Recherche en Sciences de la Santé,

    Direction Régionale de l’Ouest, Bobo-Dioulasso, Burkina Faso, 9 London School of Hygiene & Tropical

    Medicine, London, United Kingdom, 10 Kenya Medical Research Institute–Wellcome Trust Research

    Programme, Kilifi, Kenya, 11 Institute for Tropical Medicine, University of Tübingen, Tübingen, Germany,

    12 Joanna Briggs Affiliate Centre for Evidence-Based Health Care, Evidence Synthesis and Translation

    Unit, Afya Research Africa, Nairobi, Kenya, 13 Global and Tropical Health Division, Menzies School of

    Health Research and Charles Darwin University, Darwin, Northern Territory, Australia, 14 Department of

    Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California,

    United States of America, 15 Yale School of Public Health and Medicine, New Haven, Connecticut, United

    States of America, 16 Shoklo Malaria Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae

    Sot, Thailand




    Artemisinin-based combination therapies (ACTs) are the mainstay of the current treatment

    of uncomplicated Plasmodium falciparum malaria, but ACT resistance is spreading across

    Southeast Asia. Dihydroartemisinin-piperaquine is one of the five ACTs currently recom-

    mended by the World Health Organization. Previous studies suggest that young children


  • Data were pooled and analysed using nonlinear mixed-effects modelling. Piperaquine phar-

    macokinetics were described successfully by a three-compartment disposition model with

    flexible absorption. Body weight influenced clearance and volume parameters significantly,

    resulting in lower piperaquine exposures in small children (

  • • A pharmacokinetic model was developed to describe the pharmacological properties of

    piperaquine, the expected variability between patients, and the influence of biologically

    important covariates.

    • Small children had a substantially lower piperaquine exposure after recommended dos-

    ing regimens.

    • The developed pharmacokinetic model was used to derive a new optimised dose


    What Do These Findings Mean?

    • The proposed improved dose regimen of dihydroartemisinin-piperaquine is expected to

    provide equivalent piperaquine exposures safely in all patients, including in small chil-

    dren with malaria.

    • An optimised dose regimen should prolong the useful therapeutic life of dihydroartemi-

    sinin-piperaquine by increasing cure rates and thereby slowing resistance development.


    Malaria currently causes an estimated 1,200 deaths each day [1]. Most malaria-related deaths

    occur in Africa in children under the age of 5 y. In endemic areas, young children lack sufficient

    acquired immunity and are more likely to develop severe forms of the disease. Artemisinin-

    based combination therapy (ACT) is the recommended first-line treatment for uncomplicated

    Plasmodium falciparum malaria. The 3-d fixed-dose combination of dihydroartemisinin and piperaquine is one of five ACTs currently recommended by the World Health Organization

    (WHO) [2]. The rapidly eliminated dihydroartemisinin component has a very potent antima-

    larial effect and eliminates the majority of the parasite biomass during the first 3 d of treatment

    [3]. The partner drug, piperaquine, is a slowly eliminated antimalarial that kills the residual par-

    asites that remain after two asexual life cycles of exposure to dihydroartemisinin, thereby pre-

    venting recrudescent malaria. Piperaquine also prevents reinfections for approximately 1 mo

    after treatment [4–11]. The principal determinant of the therapeutic response of a slowly elimi-

    nated antimalarial drug is the duration for which the plasma (and thus free drug) level exceeds

    the minimum inhibitory concentration, which is reflected by the area under the plasma concen-

    tration–time curve, or its surrogate, the day 7 level [12].

    Although there are several producers of dihydroartemisinin-piperaquine, three main

    manufacturers are producing and distributing dihydroartemisinin-piperaquine in endemic

    countries: Sigma-Tau Pharmaceuticals produces Eurartesim, registered with the European

    Medicine Agency in 2012; Guilin Pharmaceutical produces D-Artepp; and Beijing Holley-

    Cotec Pharmaceuticals produces Duo-Cotexin. Sigma-Tau’s recommendation is a target daily

    dosage of 18 mg piperaquine phosphate per kilogram body weight across all age groups, with a

    practical weight-based dosing schedule provided [13]. Beijing Holley-Cotec provides two

    weight-based dosing schedules, one for children, with a target daily dosage of 16 mg/kg, and

    one for adults [14,15]. Both manufacturers’ dosage recommendations are based on evidence

    from the early stages of piperaquine development before there was extensive information on

    the pharmacokinetic properties of piperaquine in young children (

  • reductions in parasite numbers per asexual cycle, leaving a larger residual biomass of parasites

    for the partner drug to remove. This increases the probability of recrudescence and drives the

    spread of resistance. First artemisinin, and now piperaquine, resistance has emerged in Cambo-

    dia [16–18]. Elsewhere the dihydroartemisinin-piperaquine combination has shown excellent

    efficacy and tolerability, although young children treated with dihydroartemisinin-piperaquine

    have a 3-fold greater risk of recrudescent malaria compared with older children and adults

    [19–21]. Piperaquine is highly bound to plasma proteins (>98%), with a very large volume

    of distribution (>1